Lewis rats are highly susceptible to bacterial cell wall arthritis, but Fischer rats are relatively resistant. We have previously provided data suggesting that this difference was related to blunted hypothalamic- pituitary-adrenal axis (HPA) responsiveness in the Lewis rat. During the past year, we have continued to characterize the neuroendocrine defect in the Lewis rat compared to the Fischer rat and are relating it to the development of inflammation in response to streptococcal cell walls or lipopolysaccharide. In particular, we have continued to characterize corticotropin releasing hormone (CRH) expressed in peripheral tissues. We have demonstrated the presence of high levels in the inflamed joints of Lewis rats that contrasts with the low levels in arthritis-resistant Fischer rats. Our available data suggest that CRH is produced by macrophages and is also delivered to the inflammatory site through the peripheral nervous system. We have also demonstrated that HPA axis responses to LPS also differ markedly in the 2 rat strains. We are relating these differences in HPA axis function to the expression of various cytokine genes and cycyclooxygenase -1 and -2. These latter studies are not yet complete, but we have developed methods to quantitate the expression of cyclooxygenase-1 and -2, which we believe, like CRH, is intimately involved in regulating both inflammatory and HPA axis responses. Both CRH and COX-2 appear to be strongly downregulated by corticosteroids.